Enantiomer (-) of tenatoprazole and the therapeutic use thereof

ABSTRACT

The invention relates to enantiomer (−) of tentoprazole. The inventive enantiomer (−) of tenatoprazole, or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonyl]imidazol[4,5-b]pyridine exhibits improved pharmacokinetic properties which make it possible to use a once a day posology of a drug for relevant indications. Said invention can be used for curing digestive pathologies.

The present invention concerns tenatoprazole, and more particularly anenantiomer of tenatoprazole, and specifically a method for itspreparation and use in human or veterinary therapeutics.

Tenatoprazole, or5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4,5-b]pyridine,is described in Patent No. EP 254.588. It belongs to the group of drugsclassified under the name of “proton pump inhibitors” (PPIs), whichinhibit the secretion of gastric acid and are useful for the treatmentof gastric and duodenal peptic ulcers. Because of its relatively longelimination half-life, tenatoprazole can also be used for the treatmentof conditions such as gastro-oesophageal reflux, digestive bleeding anddyspepsia, as described in the French patent application No. FR02.13113.

The first known derivative of this series of PPIs was omeprazole,described in Patent No. EP 005.129, which has the property to inhibitthe secretion of gastric acid and is widely employed as an anti-ulcer inhuman therapeutics.

In addition to omeprazole, other PPIs are now well known and particularmention can be made of rabeprazole, pantoprazole and lansoprazole, whichall exhibit structural analogy and belong to the group ofpyridinyl-methyl-sulfinyl-benzimidazoles. These compounds are sulfoxideswhich have an asymmetry at the level of the sulphur atom, and thereforegenerally take the form of a mixture (racemic mixture or racemate) oftwo enantiomers.

Different formulations have been proposed in order to improve theproperties or the activity of PPIs. In the case of omeprazole, forexample, the PCT application WO 01.28558 describes a stable liquidformulation obtained by forming the sodium or potassium salts in situ insolution in polyethylene glycol, by action of a hydroxide on omeprazole.The medicinal product thus formulated can be used in the usualindications of PPIs.

Like omeprazole and other sulfoxides with similar structure,tenatoprazole has an asymmetric structure and may therefore exist in theform of a racemic mixture and in the form of two enantiomers withconfigurations “R” and “S”, or (+) and (−), respectively.

Recent studies have shown that unexpectedly and unlike all the otherPPIs (such as, for example, omeprazole or lansoprazole), tenatoprazolepossesses a remarkably long duration of action which is the result of alonger half-life in plasma (approximately seven times longer). Indeed,clinical data have shown that tenatoprazole induces a degree of symptomrelief and healing of gastric lesions which is superior to thoseachieved by other PPIs, and which allows for its effective use in thetreatment of diseases and conditions such as, for example, atypical andoesophageal symptoms of gastro-oesophageal reflux, digestive bleedingand dyspepsia.

Studies conducted by the applicant have unexpectedly shown that the (+)and (−) enantiomers of tenatoprazole contribute differently to theproperties of tenatoprazole and exhibit significantly differentpharmacokinetic properties. Thus, it is possible to isolate theseenantiomers and prepare medicinal products with differentpharmacokinetic profiles and specific activities. It then becomespossible to use each enantiomer more effectively for the treatment ofspecific diseases and conditions.

The present invention concerns the use of the (−) enantiomer oftenatoprazole in human or veterinary therapeutics.

One purpose of the present invention is the preparation of apharmaceutical composition comprising the (−) enantiomer oftenatoprazole in combination with one or more pharmaceuticallyacceptable excipients and substrates.

The present invention also relates to a pharmaceutical compositioncomprising the (−) enantiomer of tenatoprazole in combination with oneor more antibiotics.

A further object of the present invention is the use of the (−)enantiomer of tenatoprazole in the manufacture of a medicinal product totreat digestive diseases and conditions where the inhibition of acidsecretion must be effective and prolonged to treat, for example, thesymptoms and lesions of gastro-oesophageal reflux, or digestive bleedingrefractory to other PPIs, and especially treat these diseases andconditions in patients receiving multiple drug therapy.

A further object of the present invention is the use of the (−)enantiomer of tenatoprazole in the manufacture of a drug with asignificantly improved onset of healing as well as an increase in therate of normalization of histological changes of the gastric lesions inanimals or humans, which result in a sharp decrease in the relapse ofoesophagitis, and thus for the prevention or the treatment of therelapse of oesophagitis.

The present invention also concerns the use of the (−) enantiomer oftenatoprazole in the manufacture of a medicinal product with improvedpharmacokinetic properties that would allow taking a single dose ofmedication per day in relevant indications, and particularly in theeradication of Helicobacter pylori during the treatment of duodenalulcer, condition which usually requires two doses (morning and evening)of other PPIs.

The (−) enantiomer of tenatoprazole can be used in the form of a salt,including an alkaline or earth-alkaline metal salt and, for example, inthe form of a sodium, potassium, lithium, magnesium or calcium salt.These salts can be obtained from the (−) enantiomer of tenatoprazolethat has previously been isolated by salification according to thestandard method of the technique, for example by the action of basicmineral reagents comprising alkaline or earth-alkaline counter-ions.

The (−) enantiomer of tenatoprazole, or (−) tenatoprazole, correspondsto(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4,5-b]pyridine.It can be represented by the following general formula:

According to a preferred method of preparation, the (−) enantiomer oftenatoprazole can be obtained in an enantioselective manner under goodpurity and yield conditions, by enantioselective oxidation of thecorresponding sulphide in the presence of a specific vanadium-basedcatalyst. Such method is described in French patent application 0303914.

The sulphide used as starting material is a known product that can beprepared according to several methods described in literature, and forexample, according to the methods described in Patents No. EP 254.588and EP 103.553.

The oxidizing agent used in the method of the invention is preferably aperoxide, for example hydrogen peroxide. According to an advantageousmethod of implementation, highly concentrated hydrogen peroxide, higherthan 30% for example, is used.

According to the invention, the catalyst can be selected from Voxo-vanadium complex catalysts, such as vanadium acetylacetonate. Suchcatalysts are commercially available.

A ligand such as a Schiff base derived from a substituted salicylicaldehyde and from a chiral amino-alcohol, is preferably used incombination with the catalyst. A most preferred ligand is2,4-di-tert-butyl-6-[1-S-hydroxymethyl-2-methyl-propylimino)-methyl]-phenol.Under operating conditions, the ligand and the metallic catalyst form anasymmetric complex where the metal is oxidized by the oxidizing agent.

The reaction may be carried out in a solvent, in a neutral or weaklybasic medium, for example in methanol, tetrahydrofuran, methylenechloride, acetonitrile or toluene. The base used otherwise may be atertiary amine such as pyridine, di-isopropylethylamine ortriethylamine. The oxidation reaction is easily conducted at lowtemperatures or at room temperature.

The (−) enantiomer of tenatoprazole can be easily obtained in a pureoptical form according to the above method of synthesis.

Here, “pure optical form” means that the (−) enantiomer is substantiallyfree of the (+) enantiomer, or contains only traces of it. If relevant,salification with a base is then performed in an appropriate solvent toform a salt, and particularly an alkaline or earth-alkaline metal salt.

This form can be measured by optical rotation measurements usingstandard techniques.

For example, it is possible to prepare a solution of the desiredenantiomer at 0.25% (50 mg of a sample per 20 ml of solvent) dissolvedin dimethylformamide or acetonitrile, and using a polarimeter of acommonly employed type (e.g., Jobin Yvon). In dimethylformamide andacetonitrile, the angle of optical rotation of (−) tenatoprazole islevorotatory, and its melting point is 127-130° C. (decomposition).

The (−) enantiomer of tenatoprazole can also be obtained in a pureoptical form by well known techniques, using any appropriate method ofseparation, for example by preparative column chromatography, such aschiral chromatography or high performance liquid chromatography (HPLC).

The principle of the chiral chromatography method is based on thedifference in affinity existing between (+) and (−) enantiomers and thechiral selector of the stationary phase. This method enables theseparation of the enantiomers with a satisfactory yield.

If necessary, the racemic mixture of tenatoprazole can be obtained usingknown processes, for example according to the method described in PatentNo. EP 254.588. Thus, it can be prepared using an oxidizing agent, suchas perbenzoic acid, to treat the corresponding sulphide arising from thecondensation of a thiol and a pyridine, preferably in the presence of abase such as potassium hydroxide in an appropriate solvent, for exampleethanol, under heating.

The known method used to separate the enantiomers of tenatoprazole canprovide the isolation of the (−) enantiomer with excellent purity(chiral purity: minimum 98.8 of the surface area).

In the studies conducted by the applicant, it was confirmed that the (−)isomer of tenatoprazole obtained according to the method described inthe present invention has the “S” configuration, which means that the(+) isomer has the “R” configuration.

Pharmacological Studies

In vivo studies in rats: assessment of volume and pH of gastricsecretion.

Studies conducted by the applicant in vivo in a model of ligature of thepylorus in the rat have investigated the pharmacological effects of the(−) and (+) isomers of tenatoprazole. In this well established andvalidated model, animals are pre-treated at different time points (10,16 and 20 h) before ligature of the pylorus, and the volume and pH ofthe gastric secretions are measured 4 h after the ligature.

Significant differences between the two isomers can be observed withthis model, as summarized in the following table. Indeed, 10 h aftertreatment administration the (−) isomer remains pharmacologicallyactive. It increases the pH by 49% (p<0.01) and decreases gastricacidity by about 55% (p<0.01), as compared to the control group, whereasthe effect of the (+) isomer is no longer significant. pH Free acid (−)isomer +49% −55% (+) isomer +30% −30%

In vivo studies in dogs: assessment of the antisecretory effect.

Studies conducted by the applicant in vivo in dogs have investigated theanti-secretory effect of the (−) isomer of tenatoprazole and the (+)isomer, by measuring the intragastric pH after treatment administrationfor 6 days (10 mg/kg/day). The profile of intragastric pH during a24-hour period was recorded on the first two days of administration, onthe 6^(th) day, and two days after treatment termination. These pHvalues were compared to those measured at baseline, prior to treatmentadministration.

It was demonstrated that the (−) isomer of tenatoprazole and the (+)isomer of tenatoprazole inhibit gastric secretion in dogs. However asignificant effect can be only observed with the (−) isomer oftenatoprazole from the first day of administration, and is maintaineduntil two days after treatment termination.

The results corresponding to the pH>3 and pH>4 holding time for 24 h,expressed in percent, are described below: % of holding time for 24hours pH > 3 pH > 4 basal 21 9 1^(st) day of treatment 73 55 2^(nd) dayof treatment 82 75 6^(th) day of treatment 93 75

In vivo studies in rats: assessment of the onset of healing and theincrease of normalisation of histological changes of the lesions.

Other in vivo experiments conducted by applicant in rats havedemonstrated that the onset of healing of ulcerative lesions wassignificantly improved with the administration of the (−) enantiomer oftenatoprazole, as compared with the effects obtained with the (+)enantiomer. Thus, the effect observed with the (−) enantiomer oftenatoprazole appeared 1 day before those of the (+) enantiomer. Suchunexpected difference was also followed by a significant increase in thequality of such healing due to the increase in the normalization ofhistological changes when the (−) enantiomer was administered. Thesechanges consisted in a reduction of the ultrastructural damage resultingin a complete morphological recovery of the oesophageal epithelium.

Such pharmacological effect of the (−) enantiomer on both qualitativeand quantitative improvement will result in a significant decrease inthe number of relapses of oesophagitis.

Pharmacokinetic Studies

Studies performed by the applicant on the (−) enantiomer oftenatoprazole prepared as above have unexpectedly demonstrated that itpossesses pharmacokinetic properties which are fundamentally differentfrom those of the other PPIs or the (+) enantiomer, thus suggesting thatthe (−) enantiomer could be used in specific therapeutic indications.

Thus, the (−) enantiomer of tenatoprazole is significantly different interms of pharmacokinetic properties, as shown by the studies describedherein. This characteristic is essential, as it will provide theclinician with a medicinal product adequate for an effective treatmentof specific diseases and conditions.

More particularly, the unexpected pharmacokinetic properties of the (−)enantiomer of tenatoprazole were discovered during an extensive programof pharmacokinetic and metabolism studies in vitro and in vivo. Becauseof a variability observed in pharmacokinetics, and notably in theAUC_(0-inf) (area under the curve) and t_(1/2) (elimination half-life),the genotype of some subjects of the study was assessed in order toidentify which type of metaboliser (i.e., slow or rapid) they belongedto.

It must be pointed out that an important aspect of the metabolism ofPPIs is that they are mostly metabolised by the cytochrome CYP2C19 whosegene is located on chromosome 10. Therefore, the PPIs exhibit a “geneticpolymorphism”, that is, an activity which varies as a function of thegenotype of a patient. This results in variable plasma levels of thedrug and a susceptibility to potentially harmful drug interactions,depending on the individual concerned.

In Vitro Pharmacokinetic and Metabolism Studies

Indeed, in vitro studies conducted on the cytochromes that metabolisetenatoprazole have revealed the existence of a significant difference inthe metabolism of the (−) versus the (+) isomers, as shown in thefollowing table: Vmax (−) Vmax (+) CYP2C19 1.90 12.63

In the above table, the value Vmax is the maximal rate of metabolism(Vmax) measured as pmol/min per pmol of cytochrome. Vmax (−) is thevalue of Vmax of the (−) enantiomer of tenatoprazole.

From these results it can be concluded that the (−) enantiomer ismetabolised approximately 7 times more slowly than the (+) enantiomer.Consequently, it can be anticipated that the (−) enantiomer oftenatoprazole will have a much longer mean residence time (MRT) in thehuman body, by comparison with the (+) enantiomer.

Further, it has been shown that different cytochromes intervene in themetabolism of tenatoprazole.

The (−) enantiomer is mainly metabolised via the cytochrome CYP3A4,which can compensate for a potential deficiency or blockade ofcytochrome CYP2C19. The (+) enantiomer is metabolised via two pathways,i.e. mainly the CYP2C19 and, to a lesser extent, by CYP3A4.

In addition, it has become clear that subjects homozygous for a mutationwhich gives rise to the CYP2C19*2/*2 genotype exhibit pharmacokineticcharacteristics of tenatoprazole totally different from those seen inthe general population. The homozygous subjects have a very weakmetabolic activity of the cytochrome CYP2C19 which is responsible forthe metabolism of tenatoprazole. The analysis of plasma has shown thatthese subjects display a highly significant increase in the (+)enantiomer when compared with the (−) enantiomer. These subjects arequalified as “slow metabolisers”.

Conversely, subjects who are characterised by the CYP2C19*1/*1 genotypeare “rapid metabolisers” and display a concentration of (−) enantiomerhigher than that of the (+) enantiomer, as summarised in the followingtable: (+) Genotype Metabolic activity (−) Enantiomer EnantiomerCYP2C19*2/*2 Weak activity of Increased cytochrome CYP2C19 = “Slowmetabolisers” CYP2C19*1/*1 Normal activity of Increased cytochromeCYP2C19 = “Rapid metabolisers”

Taking into account the possible saturation of CYP2C19, it isanticipated that the potential risk of drugs interactions in patientsreceiving concomitant medications will be dramatically decreased whenthe (−) enantiomer will be administred.

In Vivo Pharmacokinetic and Metabolism Studies

Other studies performed by applicant in dogs have shown that theadministration of the (−) enantiomer of tenatoprazole resulted in adifference of rate of metabolism leading to a significantly longerhalf-life for the (−) enantiomer of tenatoprazole in comparison with the(+) enantiomer.

Clinical Studies

In order to assess the difference in pharmacokinetic characteristicsbetween the (−) enantiomer of the invention and the (+) enantiomer, apharamcokinetic study was conducted.

Said study was carried out in Caucasian subjects, after an acute andrepeated administration (7 days) of tenatoprazole. After the 7 days oftreatment, it was observed that the plasma concentration of the (−)isomer is linear with the dose, as is the case for its AUC which iscorrelated with the intra-gastric pH of the subject and thus of theactivity of the treatment. In contrast, it was observed that theevolution of the plasma concentration of the (+) isomer is not linear,and thus not predictive of the efficacy and the tolerability of thedrug. Furthermore, it was observed that the between-subject variabilityof pharmacokinetic parameters is markedly lower for the (−) isomercompared to the (+) isomer.

In another study, it was assessed that the elimination half-life of the(−) isomer of tenatoprazole is approximately 4 times shorter than thatof the (+) isomer in slow metabolisers (which are deficient in CYP2C19activity), as summarised in the following table: Slow metabolisers: T1/2(hours): (−) isomer  9.7 ± 0.9 (+) isomer 36.7 ± 4.5

Thus, the results of the above confirm that the (−) enantiomer oftenatoprazole possesses a much better predictability of action, whichwould make it possible to anticipate and limit the potential risks ofdrug interactions in patients receiving concomitant medications.

Thus, the overall conclusion of the above study is that the (−)enantiomer of tenatoprazole possesses a superior efficacy and asignificant safety profile, which will prevent from serious adverse drugreactions.

All these unexpected results have led to the proposal of isolating andadministering only one enantiomer of tenatoprazole, the (−) enantiomer,which has the following advantages:

-   -   A reduction in between-subject variations, hence a better use of        the product and a more homogenous response to treatment in all        patients;    -   An improved tissue exposure of the product, because its rate of        metabolism is slower and the mean residence time (MRT) in the        body is longer;    -   A reduction in the number of potential interactions with        concomitant medications. Indeed, the (−) isomer is metabolized        through two ways, i.e. the 2C19 and 3A4 cytochromes, which        compensates for a possible deficiency or blocking of 2C19        cytochrome.    -   An ease of use in all types of patients, whether they are slow        or rapid metabolisers. Indeed, the (−) enantiomer in a slow        metaboliser would be metabolised by cytochrome CYP3A4, thus        making it possible to achieve uniform pharmacokinetic parameters        independently of the genotype of the patients.    -   an improved efficacy/safety profile in all types of patients to        treat digestive diseases and conditions such as typical and        oesophagal symptoms of gastro-oesophagal reflux, digestive        bleeding and dyspepsia.    -   an improved onset of healing as well as an increase in the        normalization of histological changes of gastric lesions.

Furthermore, the isolation of the (−) enantiomer of tenatoprazole hasmade it possible to determine its pharmacokinetic profile and notably amean plasma half-life of approximately 10 to 12 hours at doses ofbetween 10 mg and 80 mg. In contrast, previous studies have shown thatthe racemic mixture has a mean plasma half-life of approximately 7 hoursat this range of doses.

The unexpected properties of the (−) enantiomer of tenatoprazole, andmore particularly its specific pharmacokinetic and metabolismparameters, indicate that the (−) enantiomer of tenatoprazole can beadvantageously used for the treatment of digestive diseases andconditions where it is necessary to obtain an effective and prolongedinhibition of acid secretion. This would be the case in patients withBarrett's syndrome, which causes pre-cancerous damage linked togastro-oesophageal reflux, and where the risk of oesophagealadenocarcinoma is directly proportional to the incidence, severity andduration of the episodes of gastro-oesophageal reflux.

The (−) enantiomer of tenatoprazole is also suitable for the treatmentof patients with the Zollinger-Ellison syndrome and other syndromesinvolving acid hypersecretion, and for the treatment of atypical andoesophageal symptoms of gastro-oesophageal reflux, digestive bleedingrefractory to other PPIs, and especially suitable for treatment ofpatients receiving multiple drug therapy, and especially elderlypatients, with the aim of preventing adverse events associated with druginteractions.

The (−) enantiomer of tenatoprazole can also be used, preferably incombination with one or more antibiotics, to treat ulcers in the eventof Helicobacter pylori infection, and notably to help eradicateHelicobacter pylori by facilitating the healing of the ulcer and preventrecurrence.

For the treatment of the conditions listed above, and most particularlythe Barrett and Zollinger-Ellison syndromes, and of gastro-oesophagealreflux and digestive bleeding, the (−) enantiomer of tenatoprazole canbe administered in standard forms adapted to the method ofadministration chosen, for example via the oral or parenteral routes,and preferably via the oral or intravenous routes.

For example, it is possible to use tablet or capsule formulationscontaining the (−) enantiomer of tenatoprazole as the active substance,or oral solutions or emulsions or solutions for parenteraladministration containing a tenatoprazole salt with a standard,pharmaceutically-acceptable substrate. The salt of the (−) enantiomer oftenatoprazole can be chosen, for example, from amongst sodium,potassium, lithium, magnesium or calcium salts.

An example of an appropriate formulation for tablets containing 30 mg ofthe (−) isomer of tenatoprazole in combination with pharmaceuticallyacceptable substrates and excipients, including at least one excipientgiving gastro-resistant properties to the formulation, is shown below:(−) tenatoprazole 30.0 mg lactose 40.0 mg aluminum hydroxide 17.5 mghydroxypropyl cellulose 8.0 mg talc 4.5 mg titanium dioxide 5.0 mgmagnesium stearate 2.0 mg standard excipients qs 160.0 mg

An example of a formulation for a size-2, gastro-resistant entericcapsule (capsule shell made of acetophtalate, polyvinylpyrrolidonederivatives and acrylic resins), containing 40 mg of the (−) isomer oftenatoprazole is shown below: (−) tenatoprazole  40.0 mg lactose 200.0mg magnesium stearate  10.0 mg

The dosage is determined by the practitioner as a function of thepatient's state and the severity of the condition. It is generallybetween 10 and 120 mg per day, and preferably between 10 and 80 mg perday of the (−) enantiomer of tenatoprazole. For example, it can beadministered at a rate of one daily intake of 1 or 2 unit doses (e.g.,tablets), each containing 10 to 80 mg and preferably 15 or 20 to 40 or60 mg of the active substance, for a period of time which can range from4 to 12 weeks in the context of an initial or maintenance therapy. Inthe case of a paediatric form adapted for use in young children, forexample in the form of an oral solution, the unit dose can be lower, forexample 2 or 5 mg. In the case of severe disorders, it may be effectiveto administer the medicinal product in the first instance via theintravenous route, and subsequently via the oral route. The inventionalso has the advantage of permitting effective, sequential treatmentwith the weekly administration of a single tablet containing 60 to 90mg.

One of the advantages of the present invention is that it allowstreatment of the diseases and conditions referred to above, includingthe treatment of ulcers resulting from Helicobacter pylori infection,with a dosage limited to a single dose of medication per day, unlikeother standard drugs, including standard PPIs, which require two dailydoses.

In order to illustrate the present invention, an example of preparationof the (−) enantiomer of tenatoprazole is described below.

EXAMPLE

3 L of methylene chloride and then 360 g of5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]imidazo[4,5-b]-pyridineare added in a 5 L flask. The mixture is left under stirring for 30minutes at room temperature.

700 mL of acetonitrile, 5.22 g of2,4-di-tert-butyl-6-[1-R-hydroxymethyl-2-methyl-propylimino)-methyl]-phenol,and 2.90 g of vanadyl acetylacetonate are dropped one after the other ina 2 L flask. The mixture is kept under stirring at room temperature.After an stirring for 30 min, such solution is added to the precedingone.

135 mL of hydrogen peroxide at 30% are added to this mixture understirring for 20 hours at room temperature. After separation of theaqueous phase, the organic phase is washed twice with water, then driedand concentrated under reduced pressure. 283 g of the desired enantiomerare obtained, with an enantiomeric excess higher than 80% (75% yield).Two successive recrystallisations are performed in a methanol/water ofDMF/ethyl acetate mixture and the enantiomer is obtained with anenantiomeric excess higher than 99%.

F: 127.5° C.

[α]_(D): −186.6 (DMF)

UV spectrum (methyl alcohol-water): λ_(max): 272 nm, 315 nm.

Infra-red (KBr): 3006, 1581, 1436, 1364, 1262 cm⁻¹.

NMR ¹³C (KOH, reference: sodium 3-(trimethylsilyl)-1-propane-sulfonate)δ (ppm): 13.2; 15.0; 56.6; 60.8; 62.6; 107.2; 129.5; 130.4; 131.9;135.1; 150.5; 151.4; 156.9; 160.7; 163.0; 166.6.

MNR ¹H (DMSO d₆, reference: TMS) δ (ppm): 2.20 (s, 6H), 3.70 (s, 3H),3.91 (s, 3H), 4.69-4.85 (m, 2H), 6.80 (d, J 8.5 Hz, 1H), 7.99 (d, J 8.5Hz, 1H), 8.16 (s, H), 13.92 (s, 1H).

1. The compound (−) tenatoprazole or one of its salts, substantiallyfree of the (+) enantiomer.
 2. A pharmaceutical composition comprising(−) tenatoprazole or a pharmaceutically acceptable salt thereof,substantially free of the (+) enantiomer, and one or morepharmaceutically acceptable excipients or substrates.
 3. Thepharmaceutical composition according to claim 2, wherein the (−)tenatoprazole is a pharmaceutically acceptable salt selected from thegroup consisting of alkaline and earth-alkaline metal salts.
 4. Thepharmaceutical composition according to claim 3, wherein the (−)tenatoprazole is a pharmaceutically acceptable salt selected from thegroup consisting of sodium, potassium, lithium, magnesium and calciumsalts.
 5. The pharmaceutical composition according to claim 2,comprising a unitary dose comprising from about 10 mg to about 80 mg ofactive principle.
 6. The pharmaceutical composition according to claim2, further comprising one or more antibiotics. 7-13. (canceled)
 14. Thepharmaceutical composition according to claim 3, comprising a unitarydose comprising from about 10 mg to about 80 mg of active principle. 15.The pharmaceutical composition according to claim 4, comprising aunitary dose comprising from about 10 mg to 80 mg of active principle.16. A method of treatment of digestive diseases and conditionscomprising administering to a subject in need thereof an effectiveamount of (−) tenatoprazole substantially free of the (+) enantiomer, ora pharmaceutically acceptable salt thereof.
 17. A method of treatmentaccording to claim 16, wherein the digestive diseases and conditions areselected from the group consisisting of Barrett's syndrome,Zollinger-Ellison syndrome, atypical and oesophageal symptoms ofgastro-oesophageal reflux, and digestive bleeding refractory to otherproton pump inhibitors (PPIs).
 18. A method for the treatment ofdigestive diseases and conditions comprising administering to a subjectin need thereof an effective amount of a pharmaceutical compositioncomprising (−) tenatoprazole or a pharmaceutically acceptable saltthereof, substantially free of the (+) enantiomer, and one or morepharmaceutically acceptable excipients or substrates.
 19. A method oftreatment according to claim 18, wherein the digestive diseases andconditions are selected from the group consisisting of Barrett'ssyndrome, Zollinger-Ellison syndrome, atypical and oesophageal symptomsof gastro-oesophageal reflux, and digestive bleeding refractory to otherproton pump inhibitors (PPIs).
 20. A method of treatment of an ulcerresulting from an infection by Helicobacter pylori comprisingadministering to a subject in need thereof an effective amount of (−)tenatoprazole substantially free of the (+) enantiomer, or apharmaceutically acceptable salt thereof.
 21. A method of treatment ofan ulcer resulting from an infection by Helicobacter pylori comprisingadministering to a subject in need thereof an effective amount of apharmaceutical composition comprising (−) tenatoprazole or apharmaceutically acceptable salt thereof, substantially free of the (+)enantiomer, and one or more pharmaceutically acceptable excipients orsubstrates.
 22. A method of treating or preventing the relapse ofoesophagitis comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition comprising (−)tenatoprazole or a pharmaceutically acceptable salt thereof,substantially free of the (+) enantiomer, and one or morepharmaceutically acceptable excipients or substrates.
 23. A method oftreating or preventing the relapse of oesophagitis comprisingadministering to a subject in need thereof an effective amount of (−)tenatoprazole substantially free of the (+) enantiomer, or apharmaceutically acceptable salt thereof.
 24. A method for the treatmentof digestive diseases and conditions according to claim 16, wherein theeffective amount of (−) tenatoprazole substantially free of the (+)enantiomer exhibits improved pharmacokinetic properties.
 25. The methodof claim 16, wherein the (−) tenatoprazole substantially free of the (+)enantiomer or pharmaceutically acceptable salt thereof is administeredorally.
 26. The method of claim 16, wherein the (−) tenatoprazolesubstantially free of the (+) enantiomer or pharmaceutically acceptablesalt thereof is administered via a parenteral solution.
 27. The methodof claim 25, wherein the oral administration is via tablet, capsule ororal suspension or oral emulsion.
 28. The method of claim 26, whereinthe parenteral administration is via an intravenous solution.
 29. Themethod of claim 26, wherein the parenteral solution comprises atenatoprazole salt and a pharmaceutically acceptable substrate.
 30. Themethod of claim 25, wherein the (−) tenatoprazole substantially free ofthe (+) enantiomer is administered in an amount of about 10 mg to about120 mg per day.
 31. The method of claim 30, wherein the (−)tenatoprazole substantially free of the (+) enantiomer is administeredin an amount of about 10 mg to about 80 mg per day.
 32. The method ofclaim 25, wherein the (−) tenatoprazole substantially free of the (+)enantiomer is administered once per day.
 33. The method of claim 25,wherein the (−) tenatoprazole substantially free of the (+) enantiomeris administered once per day for a period of about four to about twelveweeks.
 34. The method of claim 25, wherein the (−) tenatoprazolesubstantially free of the (+) enantiomer is administered first via anintravenous route and subsequently via an oral route.
 35. The method ofclaim 27, wherein the tablet is administered once per week and whereinthe tablet comprises about 60 mg to about 90 mg of (−) tenatoprazolesubstantially free of the (+) enantiomer
 36. A combination therapy forthe treatment of digestive disease and conditions comprising apharmaceutically effective amount of (−) tenatoprazole substantiallyfree of the (+) enantiomer or pharmaceutically acceptable salt thereofand a second agent selected from the group consisting of a proton pumpinhibitor (PPI).
 37. The method of claim 36, wherein the proton pumpinhibitor (PPI) is selected from the group consisting of omeprazole,rabeprazole, pantoprazole, and lansoprazole.